In the past five years there has been a marked increase in our knowledge of human Fc-gamma receptors which we now understand as three families of related, but richly diverse, molecules. The various FC-gammaR forms, isoforms and allelic forms, -- have different functional capacities. These advances bring into focus our hypotheses: 1) that abnormal Fc-gammaR function (both genetically determined and disease-acquired) is a contributory factor in autoimmune immune complex disease pathogenesis; 2) that the presence/ expression of different FC-gammaR structural forms is both genetically determined (at the level of allelic forms) and under differential regulational control (at the level of family and isoform expression); 3) that the different capacities of the Fc-gammaR forms preferentially associated with or expressed in immunogenetically defined normals and in SLE patients contributes substantially to the abnormal Fc- gammaR function. Preliminary data indicate that the Fc-gammaRI is a compelling candidate responsible for Fc-gammaR dysfunction in immunogenetically defined normals and SLE. Receptor specific studies have shown that Fc-gammaRI is uniquely associated with this Fc-gammaR abnormality which may be related to newly discovered Fc-gammaRI isoforms and allelic forms. Therefore, the specific aims of this proposal are: 1. to define the different structural isoforms and allelic forms of Fc- gamma receptors, focussing on FC-gammaRI; 2. to define the functional capacities of each of these structural forms; 3. to define the mechanisms mediating these different functional capacities; 4. to define the relative expression of the families and their isoforms in, and to determine the association of allelic forms with, Fc-y receptor dysfunction in immunogenetically defined normals and in autoimmune diseases such as SLE. The efficiency of handling immune complexes by Fc-gamma receptors is critical in determining the predisposition to immune complex disease. Thus, genetically associated abnormalities in Fc-gamma receptor specific function may be a significant risk factor for SLE. This proposal will focus on fundamental Fc-gamma receptor structure-function relationships, emphasizing the Fc-mediated defects in phagocyte function, so that we can assess the impact of Fe-gamma receptor polymorphisms on immune complex interactions. Identification of genetic risk factors for SLE and appropriate regulation of specific Fc-gamma receptor isoform expression with cytokines or other agents will allow novel and effective therapy in SLE.